Faculty Bibliography

OBJECTIVE: To determine how two different types of iodinated contrast media (CM), low-osmolar ionic dimer ioxaglate (Hexabrix) and iso-osmolar non-ionic dimer iodixanol (Visipaque), affect multiple indices of hemostasis. BACKGROUND: In vitro models demonstrate differential effects of ionic and non-ionic CM on markers of hemostasis. METHODS: This blinded endpoint trial randomized 100 patients to ioxaglate or iodixanol. The primary endpoint was change in endogenous thrombin potential (ETP) following diagnostic angiography. Secondary endpoints included change in markers of fibrinolysis [tissue plasminogen activator (tPA) and plasminogen activator inhibitor 1 (PAI-1)] and platelet aggregation following diagnostic angiography and percutaneous coronary intervention (PCI) with bivalirudin. Data are presented as median [interquartile range]. RESULTS: ETP significantly decreased after diagnostic angiography in both ioxaglate (baseline 1810 nM*minute [1540-2089] to post-angiography 649 nM*minute [314-1347], p < 0.001) and iodixanol groups (baseline 1682 nM*minute [1534-2147] to post-angiography 681 nM*minute [229-1237], p < 0.001), but the decrease was not different between CM (p = 0.70). There was a significant increase in ETP during PCI (n = 45), despite the use of bivalirudin, suggesting a prothrombotic effect of PCI (post-angiography 764 nM*minute [286-1283] to post-PCI 1081 nM*minute [668-1552], p = 0.02). There were no significant differential effects on tPA, PAI-1, and markers of platelet activity. CONCLUSION: There were no significant differential effects between ioxaglate and iodixanol. Both CM led to significant reductions in thrombin generation and no significant effects on fibrinolytic activity or platelet activity, thereby contributing to a favorable antithrombotic milieu. (c) 2015 Wiley Periodicals, Inc.

BACKGROUND: Preoperative anemia is a well-established risk factor for short-term mortality in patients undergoing non-cardiac surgery, but appropriate thresholds for transfusion remain uncertain. The objective of this study was to determine long-term outcomes associated with anemia, hemorrhage and red blood cell transfusion in patients undergoing non-cardiac surgery. METHODS: We performed a long-term follow-up study of consecutive subjects undergoing hip, knee, and spine surgery between November 1, 2008 and December 31, 2009. Clinical data were obtained from administrative and laboratory databases, and retrospective record review. Pre-operative anemia was defined as baseline hemoglobin <13 g/dL for men and <12 g/dL for women. Hemorrhage was defined by ICD-9 coding. Data on long-term survival were queried from the Social Security Death Index (SSDI) database. Logistic regression models were used to identify factors associated with long-term mortality. RESULTS: 3,050 subjects underwent orthopedic surgery. Pre-operative anemia was present in 17.6% (537) of subjects, hemorrhage occurred in 33 (1%), and 766 (25%) received >/=1 red blood cell transfusion. Over 9,015 patient-years of follow up, 111 deaths occurred. Anemia (HR 3.91, CI 2.49 - 6.15) and hemorrhage (HR 5.28, CI 2.20 - 12.67) were independently associated with long-term mortality after multivariable adjustment. Red blood cell transfusion during the surgical hospitalization was associated with long-term mortality (HR 3.96, CI 2.47 - 6.34), which was attenuated by severity of anemia (no anemia [HR 4.39], mild anemia [HR 2.27], and moderate/severe anemia [HR 0.81], P for trend 0.0015). CONCLUSIONS: Preoperative anemia, perioperative bleeding and red blood cell transfusion are associated with increased mortality at long-term follow up after non-cardiac surgery. Strategies to minimize anemia and bleeding should be considered for all patients and restrictive transfusion strategies may be advisable. Further investigation into mechanisms of these adverse events is warranted.

Heart failure continues to be a leading cause of morbidity and mortality throughout the United States. The pathophysiology of heart failure involves activation of complex neurohormonal pathways, many of which mediate not only hypertrophy and fibrosis within ventricular myocardium and interstitium, but also activation of platelets and alteration of vascular endothelium. Platelet activation and vascular endothelial dysfunction may contribute to the observed increased risk of thromboembolic events in patients with chronic heart failure. However, current data from clinical trials do not support routine use of chronic antiplatelet or oral anticoagulation therapy for ambulatory heart failure patients without other indications (atrial fibrillation and/or coronary artery disease) as the risk of bleeding seems to outweigh the potential benefit related to reduction in thromboembolic events. In this review, we consider the potential clinical utility of targeting specific pathophysiological mechanisms of platelet and vascular endothelial activation to guide clinical decision making in heart failure patients.

The cardioprotective mechanisms of colchicine in patients with stable ischemic heart disease remain uncertain. We tested varying concentrations of colchicine on platelet activity in vitro and a clinically relevant 1.8-mg oral loading dose administered over 1 h in 10 healthy subjects. Data are shown as median [interquartile range]. Colchicine addition in vitro decreased light transmission platelet aggregation only at supratherapeutic concentrations but decreased monocyte- (MPA) and neutrophil-platelet aggregation (NPA) at therapeutic concentrations. Administration of 1.8 mg colchicine to healthy subjects had no significant effect on light transmission platelet aggregation but decreased the extent of MPA (28 % [22-57] to 22 % [19-31], p = 0.05) and NPA (19 % [16-59] to 15 % [11-30], p = 0.01), platelet surface expression of PAC-1 (370 mean fluorescence intensity (MFI) [328-555] to 333 MFI [232-407], p = 0.02) and P-selectin (351 MFI [269-492] to 279 [226-364], p = 0.03), and platelet adhesion to collagen (10.2 % [2.5-32.6] to 2.0 % [0.2-9.5], p = 0.09) 2 h post-administration. Thus, in clinically relevant concentrations, colchicine decreases expression of surface markers of platelet activity and inhibits leukocyte-platelet aggregation but does not inhibit homotypic platelet aggregation.

BACKGROUND: Patients undergoing cardiovascular procedures remain at increased risk for myocardial infarction, stroke, and cardiovascular death. Risk factor control in this patient population remains suboptimal and would likely benefit from strategies targeting education, lifestyle, and healthy behaviors. DESIGN: The IMPACT trial is a 400-subject prospective randomized trial designed to compare different cardiovascular prevention strategies in subjects following a cardiovascular intervention. The trial began enrollment in the Spring of 2012 and is randomizing subjects in a 1:1:1 manner to usual care, a one-time cardiovascular prevention consult, or a one-time cardiovascular prevention consult plus behavioral intervention program (telephone-based motivational interviewing and tailored text messages) over a 6-month period. The primary end point is non-high-density lipoprotein cholesterol. Secondary end points include other plasma lipid values, metabolic risk, smoking cessation, physical activity, dietary intake, medication use and adherence, and quality of life. CONCLUSIONS: The IMPACT trial provides data on different management strategies for risk factor optimization in subjects following cardiovascular procedures. The results will provide a platform for the continued development of novel multidisciplinary interventions in this high-risk population.

Regulation of integrins is critical for lymphocyte adhesion to endothelium and trafficking through secondary lymphoid organs. Inside-out signaling to integrins is mediated by the small GTPase Rap1. Two effectors of Rap1 regulate integrins, RapL and Rap1 interacting adaptor molecule (Riam). Using mice conditionally deficient in both Rap1a and Rap1b and mice null for Riam we show that the Rap1/Riam module is not required for T or B cell development but is essential for efficient adhesion to ICAM-1 and VCAM-1 and for proper trafficking of lymphocytes to secondary lymphoid organs. Interestingly, in Riam deficient mice, whereas peripheral lymph nodes (pLNs) were depleted of both B and T cells and recirculating B cells were diminished in the bone barrow (BM), the spleen was hypercellular, albeit with a relative deficiency of marginal zone B cells. The abnormality in lympyhocyte trafficking was accompanied by defective humoral immunity to T cell-dependent antigens. Platelet function was intact in Riam deficient animals. These in vivo results confirm a role for Riam in the regulation of some, but not all, leukocyte integrins and suggest that Riam-regulated integrin activation is required for trafficking of lymphocytes from blood into pLNs and BM where relatively high shear forces exist in high endothelial venules and sinusoids, respectively.

BACKGROUND: Atherosclerosis is a systemic vascular disorder, involving multiple arterial territories. This project sought to investigate the relationship between lower extremity peripheral artery disease (PAD) and carotid artery stenosis (CAS) in a large self-referred population. METHODS: Data from the ankle brachial index (ABI) and carotid duplex ultrasound were analyzed from 3.67 million US subjects in the Life Line Screening program between 2004 and 2008. PAD was defined by ABI<0.9 and CAS was defined by greater than 50% stenosis. Multivariate logistic regression analysis was used to estimate odds of CAS by PAD status and severity. RESULTS: Mean age of the population was 63.7 +/- 10.6 years and 64% were women. The prevalence of PAD and CAS was 4.1% and 3.9%, respectively. Subjects with PAD had a higher prevalence of CAS than those without PAD (18.8% vs. 3.3%, P < 0.0001). In multivariate analysis, PAD was associated with greater odds of CAS (OR 3.28, 95% CI 3.22-3.34). Both symptomatic (OR 3.66, 95% CI 3.58-3.75) and asymptomatic PAD (OR 2.91, 95% CI 2.84-2.98) was associated with CAS. Increasing severity of PAD was associated with greater odds of CAS (OR 2.32, 3.61, 4.19, 5.14, and 7.59 for ABI categories 0.81-0.90, 0.71-0.80, 0.61-0.70, 0.41-0.60,